tbuckley/cabot-search huggingface dataset:
A phase I trial of sequential dosing of sonidegib and pembrolizumab in advanced solid tumors (aST) and non–small-cell lung cancer (NSCLC).
Authors: Mohamed Shanshal, Nathan R. Foster, Yanyan Lou, Yujie Zhao, Mahesh Seetharam, Aaron Scott Mansfield, Konstantinos Leventakos, Mojun Zhu, Kimberly O. Steinert, Elizabeth Mikula, Qian Shi, Sani Haider Kizilbash, Haidong Dong, Alex A. Adjei, Wen Wee Ma
Journal: Journal of Clinical Oncology (2023)

9093 Background: Pembrolizumab interrupts PD-1/-L1 interaction and is efficacious in many cancers. However, resistance invariably emerges in the majority of patients. Potential mechanisms include activation of compensatory pathways. The inhibition of sonic hedgehog signaling (sHH) was previously shown to induce intra-tumoral (IT) infiltration by CD4+, CD8+ and HLA-DR class II cells. Our preclinical data showed sHH inhibitor enhanced IT penetration by monoclonal antibodies and induced PD-L1 expression. We conducted a phase I study using a novel sequential pulse dosing of sonedegib followed by pembrolizumab in aST with an expansion cohort to determine the maximum tolerated dose (MTD), tolerability and preliminary efficacy. Methods: The dose escalation utilized a 3+3 design to determine the MTD and proceeded to expansion cohort upon determination of the MTD. Patients enrolled to each dose level were observed for dose limiting toxicities (DLTs) during the 1 st cycle. The expansion cohort consisted of NSCLC and head/neck squamous cell carcinoma (HNSCC) previously treated by anti-PD1/-L1. The recommended phase 2 dose (RP2D) was determined following the review of the toxicity profile of the combination from all cycles. The study treatment consisted of sonidegib oral daily from day 1 to 8 and pembrolizumab I.V. 200 mg on day 8 on an every 3-week cycle. The sonidegib dose levels explored were 400, 600 and 800 mg. Archival tumor and blood specimens were collected for correlative studies. Adverse events (AEs) were categorized and graded per CTCAE v5.0, and tumor response by RECIST v1.1. Results: The study enrolled a total of 33 patients and 29 received treatment (13 in escalation and 16 in expansion), including patients with NSCLC, HNSCC, skin cancer, gastric cancer and melanoma. The enrollment to the NSCLC cohort is complete and HNSCC continues. No DLT was encountered during dose escalation and the MTD was not reached. The highest planned dose level was selected to proceed to expansion (sonidegib 800mg days 1-8 in combination with pembrolizumab I.V. 200 mg on day 8 on an every 3-week cycle). The expansion cohort proceeded to enroll 15 patients evaluable for AEs (10 NSCLC and 5 HSNCC). Grade 3 and above treatment-related AEs across all patients were hyperglycemia, fatigue, dyspepsia, abdominal pain. The mature efficacy data will be reported at the meeting. Conclusions: The study successfully determined the RP2D of sonidegib when dosed sequentially with pembrolizumab in advanced solid tumors. The AE profile of the combination is similar to that for respective agents given individually. The efficacy data among anti-PD1/-PDL1-treated NSCLC will be reported at the meeting. Clinical trial information: NCT04007744 .
AXL pathway as a target to overcome resistance to PARP inhibitors in high-grade serous ovarian (HGSOC) and triple-negative breast cancer (TNBC) cell lines.
Authors: Jose Alejandro Perez-Fidalgo, Juan Jose Martinez Pretel, Paloma Sanchez Serrano, Victoria Heredia, Jan Hochstadt, Marta Mendiola, Andres Redondo, Lidia Gonzalez Villena, Miriam Ruiz Linuesa, Begona Pineda
Journal: Journal of Clinical Oncology (2023)

e17502 Background: PARP inhibitors (PARPi) as olaparib (OLA) have become the new standard in maintenance treatment in high grade serous ovarian carcinoma (HGSOC) and triple negative breast cancer (TNBC). Thus there is an important need to identify the mechanisms for PARPi resistance and the strategies to overcome it. Our aim is to intervene in vitro AXL, a receptor tyrosine kinase, linking its function to the OLA-resistance mechanism and assess its suitability as a therapeutical target to overcome PARPi-resistance. Methods: Three cell lines, 2 from HGSOC (PEO1-S and Kuramochi-S) and 1 from TNBC (MDA-MB-231-S) were selected, isogenic resistant pairs generated in vitro by pulsed exposure to OLA (PEO1-R) or by exposure to growing concentrations of OLA (Kuramochi-R and MDA-MB-231-R) were obtained. Resistance was confirm by the comparison of IC50 of OLA in -S vs -R lines. AXL expression was assessed by western blot (WB). Cells were treated with OLA before and after the downregulation of AXL expression by a specific siRNA. Cell viability was assessed by MTT assay and DNA damage by the evaluation of markers by western blot (WB). Results: AXL expression was maintained upon OLA treatment in all 3 resistant cell lines. However, AXL expression was reduced upon OLA exposure in 3 sensible parental cell lines. AXL silencing (Si) lead to a significantly decrease of OLA IC50 in all 3 sensitive and resistant cell lines. For sensitive cell lines, IC50 of OLA was in 1) PEO1S with control (scramble) was 5.79 mM vs 2.24 mM after silencing with siRNA, p &lt; 0.0001; 2) Kuramochi-S scramble OLA IC50 was 481.8 mM vs 199.7 mM with siRNA, p &lt; 0.0001 and 3) MDA-MB-231-S with control of scramble the OLA IC50 was 61.62 mM vs 26.21 mM with siRNA, p = 0.001. For resistant cell lines, 4) PEO1R control with scramble 91.49 mM vs siRNA 45.72 mM, p &lt; 0.0001; 5) Kuramochi-R scramble OLA IC50 579.8 mM vs 219.8 mM with siRNA, p = 0.0008 and 6) 231-R scramble OLA IC50 68.22 mM vs 9.247 mM with siRNA, p &lt; 0.0001. These results suggest that AXL downregulation increases sensitivity to OLA in both sensitive and resistant cell lines. Histone γ-H2AX was analysed pre and post silencing and both increased when treating with OLA, especially when AXL was downregulated in alll three resistant cell lines. Conclusions: This in vitro study suggest a potential role of AXL in OLA resistance and AXL downregulation migh represent a potential mechanism to overcome resistance to OLA in ovarian and TNBC cell lines.
Rates of routine cancer screening compared with pre-pandemic levels.
Authors: Allison H Oakes, Kelly Boyce, Catherine Patton, Sanjula Jain, Cindy Revol
Journal: Journal of Clinical Oncology (2023)

10573 Background: The COVID-19 pandemic caused significant disruptions to healthcare delivery in the US due to mandatory stay-at-home orders and patient fears about visiting healthcare facilities. A logical consequence, many forms of healthcare use, including cancer screenings, sharply decreased in early 2020. Early studies suggest that cancer screening rebounded through the summer of 2020; however, &gt; 2 years removed from the start of the pandemic, the long-term impact of missed screenings is unknown. The objective of this study was to examine trends in breast, cervical, and colorectal cancer screening from 2017-2022. Methods: This cross-sectional study used the Trilliant Health national all-payer claims database to analyze calendar year quarterly medical claims from Q1 2017- Q2 2022. We limited the study sample to those aged 21-85, the guideline-concordant target populations for the screening procedures. For breast and cervical cancer, we limited our sample to women. Using Current Procedural Terminology (CPT) codes, we calculated the quarterly number of individuals, per 100,000 eligible beneficiaries, who received screening for breast cancer, cervical cancer, and colorectal cancer. Percentage change in screening tests was compared. Results: In total, the analysis included &gt; 300M unique individuals. For breast cancer, the median quarterly rate of pre-pandemic screening mammography was 8013 per 100k beneficiaries, which declined to 4,884 in Q2 of 2020—a 39% decrease. Screening mammography rebounded to pre-pandemic levels by Q3 and Q4 of 2020 but declined to a median rate of 7,314 per 100,000 beneficiaries in Q2 2022, with quarterly deficits ranging from 4-16%. For cervical cancer, the median quarterly rate of pre-pandemic screening was 5,469 per 100k beneficiaries. The rate of cervical cancer screening fell to 3,550 in Q2 of 2020—a 35% decline. By Q3 2020, cervical cancer screening rebounded toward the pre-pandemic median, then progressively declined to 4,557 per 100k beneficiaries by Q2 2022. Over the same time period, colorectal cancer screening decreased from a pre-pandemic median of 3,111 per 100k beneficiaries to 1,731 in Q2 of 2020—a 44% difference. From Q3 2020 to Q1 2022, the quarterly colorectal cancer screening rate remained 10-17% below pre-pandemic levels, but returned to 3,047 per 100k in Q2 2022, only 2% below the pre-pandemic median. Conclusions: Across the three studied cancer types, population-based screening remains below pre-pandemic levels. In agreement with other research, we find that screening quickly rebounded following the initial stages of the pandemic; however, the longer follow-up time reveals that gaps in preventive cancer screening returned and worsened. Underutilization of recommended cancer screenings will likely result in an increase in later-stage initial diagnoses and excess mortality from cancer in the future.
AI-based identification of FGFR3 mutation status from routine histology slides of muscle-invasive bladder cancer.
Authors: Charlie Saillard, Pierre-Antoine Bannier, Philipp Mann, Charles Maussion, Christian Matek, Arndt Hartmann, Markus Eckstein
Journal: Journal of Clinical Oncology (2023)

e16580 Background: Gain of function mutations of the FGFR3 gene have been reported to be important driver mutations in a subset of muscle-invasive bladder urothelial cancer (MIBC). Subsequently, gene specific kinase inhibitors (e.g., erdafitinib) have been developed to target FGFR3 mutant metastasized MIBC with promising clinical activity. FGFR3 mutational status testing is required for erdafitinib treatment, but FGFR3 mutations are rare in metastatic MIBC (10-15%). Thus, cheap and fast pre-screening tools such as artificial intelligence (AI) based image classifiers could help to reduce turnover times of FGFR3 mutational testing and save costs arising from universal mutational testing. Herein, we propose an AI-based approach to identify MIBC FGFR3 mutated patients on routine histological slides. Methods: Slides from 612 patients with MIBC from two different sources (CCC-EMN Erlangen cohort n = 239, mutant = 20; TCGA-BLCA n = 373, mutant = 50) were used. The CCC-EMN cohort was used as a discovery set while TCGA-BLCA was used as an independent validation set. A two-step AI model was used to 1) extract features from each slide and 2) predict FGFR3 status from these features. The AUC, sensitivity and specificity were used as metrics to assess the performance of our model. Most predictive regions of FGFR3 mutation were reviewed by an expert pathologist. Results: The model reached an AUC/Sensitivity/Specificity of 0.82 [0.76-0.87] / 0.90 [0.82-0.97] / 0.57 [0.53-0.62] on TCGA-BLCA, substantially improving upon results previously reported on the same cohort (Loeffler et al. 2021: AUC = 0.70). Most predictive regions of FGFR3 mutation revealed monomorphous conventional urothelial tumor morphology and low desmoplastic tumor stroma content, while least predictive regions contained pleomorphic tumor morphology and high amounts of desmoplastic tumor content. Conclusions: By ruling out 57% of MIBC FGFR3 wild type tumors with high sensitivity, our model is the first to reach valuable performance for clinical use. Consequently, this study paves the way for the development of FGFR3 pre-screening tools to ease the management of patients with MIBC.
Predictive biomarkers for treatment with amivantamab plus lazertinib among <i>EGFR</i>-mutated NSCLC in the post-osimertinib setting: Analysis of tissue IHC and ctDNA NGS.
Authors: Benjamin Besse, Christina S Baik, Melina Elpi Marmarelis, Joshua K. Sabari, Koichi Goto, Catherine A. Shu, Jong-Seok Lee, Sai-Hong Ignatius Ou, Byoung Chul Cho, Saiama Naheed Waqar, Aurélie Swalduz, Pascale Tomasini, Joshua Michael Bauml, Joshua C Curtin, Songbai Wang, Tim Jatkoe, Michael Gormley, Leonardo Trani, Roland Elmar Knoblauch, Enriqueta Felip
Journal: Journal of Clinical Oncology (2023)

9013 Background: Amivantamab (ami) is a bispecific antibody targeting EGFR and MET with immune cell-directing activity, and lazertinib (laz) is a brain-penetrant, third-generation EGFR tyrosine kinase inhibitor. In a previous report, the overall response rate (ORR) of ami+laz in the post-osimertinib (osi) setting was 36%, with median duration of response of 9.6 months (Bauml JCO 2021; 39:15_suppl, 9006). Exploratory analyses suggested certain immunohistochemistry (IHC) and ctDNA-based next-generation sequencing (NGS) biomarkers may enrich for response. A prospective study was conducted to further evaluate these potential biomarkers. Methods: CHRYSALIS-2 (NCT04077463), an ongoing phase 1/1b study, examines the efficacy (ORR per RECIST v1.1) of ami+laz in patients (pts) with EGFR-mutated NSCLC. Cohort D enrolled osi-relapsed, chemotherapy-naïve pts with EGFR exon 19 deletion or L858R mutated advanced NSCLC who had tumor tissue for IHC staining and plasma for ctDNA NGS collected after their most recent therapy. Training and validation subsets identified biomarker criteria and predictive validity, respectively. A Bayesian posterior probability (biomarker positive group ORR is ≥35% and negative group ORR is ≤20%) was predefined to be ≥85% for acceptance. Results: There were 101 response-evaluable pts enrolled in Cohort D. A total of 87 pts had detectable baseline ctDNA and 77 pts had evaluable MET IHC. The training set (n = 50) identified IHC-based MET expression of 3+ staining on ≥25% of tumor cells (MET+) as a potential predictive biomarker, and the validation set (n = 27) confirmed these results. Of those with MET IHC data, 28/77 (36%) were MET+. The overall ORR for MET+ was 61% (95% CI, 41–78) and 12% (95% CI, 5–25) for MET-, with median PFS for MET+ not reached (95% CI, 4.3–NE) vs 4.1 months (95% CI, 2.8–5.7) for MET-. NGS evaluation of ctDNA did not identify predictive biomarkers meeting predetermined criteria. Of note, only 1 pt was identified by ctDNA as having MET amplification (the pt was also MET+ by IHC). Further details will be provided at the time of presentation. Conclusions: MET+ by IHC may be a predictive biomarker for response to ami+laz in the post-osi, chemotherapy-naïve setting. In contrast, molecular profiling with ctDNA failed to identify a subgroup of pts more likely to benefit. Ami+laz represents a potential chemotherapy-free option for pts with EGFR-mutated advanced NSCLC who have progressed on osi and are also MET+ by IHC. Clinical trial information: NCT04077463 .
Quality care of patients with HR+/HER2- breast cancer: Insights from an implementation science program.
Authors: Kelly E. McKinnon, Joyce O'Shaughnessy, Lindsay Gurska, Jeffrey D. Carter, Cherilyn Heggen
Journal: Journal of Clinical Oncology (2023)

e18756 Background: Oral oncolytics have transformed the treatment landscape of HR+/HER2- breast cancer, shifting the responsibility for medication adherence and side effect management to patients. To optimize patient outcomes, collaborative patient-provider education on treatment expectations, adverse event management, and shared decision-making is imperative. Methods: From 11/2021 to 2/2022, HR+/HER2- breast cancer patients (N = 55) and health care professionals (HCPs) (N = 69) who treat breast cancer from 5 community practices were surveyed on attitudes, values, and challenges related to treatment, adherence, and adverse event management on oral therapies. HCPs (N = 59) participated in audit-feedback (AF) sessions to reflect on their own practice and develop action plans to improve care, which were implemented in subsequent collaborative patient-provider learning sessions. Informed by survey findings and insights from patient focus groups a, a point-of-care oral oncolytic toolkit was disseminated to support patients and providers in effective communication, treatment adherence, and side effect management. Results: In surveys, HCPs and patients reported side effects of medication as the top challenge impacting treatment adherence, with fatigue (33%), nausea/vomiting (28%), and hair loss (28%) the most challenging side effects. Notably, 46% of HCPs reported inadequate time to discuss patient goals, preferences and concerns as the biggest barrier for shared decision-making, and 15% of patients reported their doctor does not always ask about goals, preferences, and concerns. Reflection on survey and focus group insights in AF sessions enabled providers to develop and implement action plans including the provision of patient education resources on medication adherence and side effect recognition and management, scheduling adequate follow-up appointments to ensure side effect management and medication compliance, and engaging in shared decision-making. In patient-provider collaborative sessions, patients demonstrated substantial knowledge gains in how to communicate, recognize, and manage side effects associated with treatment, and providers committed to continuing patient education. Conclusions: Through a combination of a patient and provider survey study, patient focus groups, HCP AF sessions, and collaborative patient-provider learning sessions, action plans and education resources were developed and implemented to support the provision of effective treatment management for HR+/HER2- breast cancer. The methods and findings of this study represent key opportunities for improvement in caring for patients with HR+/HER2- breast cancer. Study Sponsor Statement: This activity is supported by educational grants from Lilly and Novartis Pharmaceuticals Corporation, who had no role in the study design, execution, analysis, or reporting.
Baseline circulating tumor cell (CTC) count as a prognostic marker of overall survival (OS) in metastatic hormone sensitive prostate cancer (mHSPC): Results from SWOG S1216, a phase III randomized trial of androgen deprivation plus orteronel (cyp17 inhibitor) or bicalutamide.
Authors: Amir Goldkorn, Catherine Tangen, Melissa Plets, Daniel Bsteh, Tong Xu, Jacek K. Pinski, Sue Ingles, Timothy Junius Triche, Gary R. MacVicar, Daniel A. Vaena, Anthony W. Crispino, David James McConkey, Primo N Lara, Maha H. A. Hussain, David I. Quinn, Tanya B. Dorff, Ian Thompson, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2023)

5080 Background: Biomarkers are needed to predict clinical outcomes in mHSPC. We previously reported that baseline CTC counts in S1216 were prognostic of PSA response and disease progression ( ASCO 2020; CCR 2021). However, the trial’s primary overall survival (OS) endpoint was not yet mature at that time. Here we present the final results of S1216 using all available samples to assess the prognostic value of CTC counts for response, progression, OS, and treatment arm interactions. Methods: In S1216, peripheral blood was drawn with informed consent at registration (baseline) and at progression to metastatic castrate resistant prostate cancer (mCRPC). CTCs were enumerated on the FDA-cleared CellSearch platform (Menarini). CTC counts were evaluated for associations with 3 pre-specified trial endpoints: 7-month PSA (7mPSA) ≤ 0.2 ng/ml vs. 0.2–4.0 vs. &gt; 4.0 using a generalized logit model; and progression-free survival (PFS) and OS using Cox regression. Results: From 2014 to 2021, 503 evaluable samples were collected at baseline and 93 at progression. Baseline CTC count was ≥5 in 11.9% of samples, 1-4 in 19.3%, and 0 in 66.8%. Comparing men with 0 vs. ≥5 CTCs at baseline, those with 0 CTCs were significantly more likely to attain a complete PSA response and had significantly lower risk of a PFS event and death after adjusting for clinical covariates (disease burden, bone metastases, age, race, alkaline phosphatase, hemoglobin, PSA, treatment arm). These associations were not modified by treatment arm. Progression CTCs &lt;5 vs. ≥5 also were prognostic of OS (logrank p=0.001), consistent with prior findings in mCRPC. Same-patient CTC counts in matched baseline-progression pairs (n=61) were highly correlated (Spearman p&lt;0.001). Conclusions: CTC count at the start of treatment for mHSPC was highly prognostic of PSA response, PFS, and OS; associations that held in both treatment arms. Moreover, baseline CTC count strongly correlated with progression count, suggesting that mild vs. aggressive disease phenotypes may persist from mHSPC to mCRPC. This evidence from a large prospective phase 3 trial suggests that baseline CTC count is a valuable prognostic marker in men initiating therapy for mHSPC, discriminating those likely to experience favorable vs. unfavorable response and OS. [Table: see text]
The role of volume of disease for treatment selection in patients with metastatic castration sensitive prostate cancer (mCSPC): A living meta-analysis.
Authors: Syed Arsalan Ahmed Naqvi, Irbaz Bin Riaz, Huan He, Manal Imran, Jacob Orme, Daniel S Childs, Praful Ravi, Syed A. Hussain, Parminder Singh, Alan Haruo Bryce
Journal: Journal of Clinical Oncology (2023)

5088 Background: Previous evidence suggests that there may be no additional benefit of triplet therapy in low volume disease based on limited data. Therefore, we investigated the efficacy of triplet therapy as compared to docetaxel (D) and androgen pathway inhibitor (API) doublets by volume of disease using the most up to date results from the ARASENS trial. Methods: Phase III randomized controlled trials (RCTs) assessing treatment intensification with API, and/or D in patients with mCSPC were included. Precomputed hazard ratios (HR) with 95% confidence intervals (CI) for OS were pooled using an inverse-variance approach. A DerSimonian-Laird random-effects meta-analysis was conducted to assess the efficacy of triplet therapy compared to D doublet therapy. P-value of interaction was computed to assess difference between high (HV) and low volume (LV) disease subgroups (P int &lt;0.1 - statistical significance). Additionally mixed treatment comparisons were computed using network meta-analysis (NMA) to assess the comparative effectiveness of triplet therapy compared to API doublets by volume of disease. Results: Pairwise meta-analysis included a total of 3 RCTs (ARASENS, PEACE-1, ENZAMET) with 2518 patients (HV: 1820; LV: 698) as shown. In patients with HV disease, 385 (43%) and 484 (53%) deaths were observed with triplet therapy, and D doublet, respectively. Triplet therapy significantly improved OS as compared to D doublet in HV (HR: 0.73; 95% CI: 0.64-0.84). In patients with LV disease, 73 (20%) and 94 (28%) deaths were observed with triplet therapy, and D doublet, respectively. Triplet therapy significantly improved OS as compared to D doublet in LV (HR: 0.71; 95% CI: 0.52-0.97). There was no statistically significant interaction by volume of disease for triplet therapy vs. D doublet (P int : 0.86). NMA including 10 clinical trials and over 11500 patients updated as of 13 th Feb 2023 showed that in HV mCSPC, triplet therapy was ranked as potentially the most efficacious treatment option and may improve OS compared to API doublet therapy (HR: 0.83; 95% CI: 0.66-1.03). In LV mCSPC, API doublet therapy was ranked as potentially the most efficacious treatment followed by triplet therapy. There was no significant difference between triplet therapy and API doublet therapy (HR: 1.12; 95% CI: 0.74-1.12). Conclusions: These results underscore that triplet therapy may be preferred in mCSPC patients with HV disease whereas API doublet therapy may be preferred in LV disease. [Table: see text]